The Molecular Basis of Cancer

Front Cover
IFC
The Molecular Basis of Cancer
Copyright
Dedication
Contributors
Preface
Contents
I Carcinogenesis and cancer Genetics
	Chapter 1 - Cancer: A Genetic Disorder
		The Discovery of Cellular Oncogenes
		Multistep Tumorigenesis
		The Discovery of Tumor Suppressor Genes
		Guardians of the Genome
		Epigenetic Mechanisms Leading to Loss of Gene Function
		Immortalized Proliferation
		Non-genetic Mechanisms Accelerating Multistep Tumor Progression
		Invasive and Metastatic Behaviors
		Other Phenotypes of Neoplasia
		References
	Chapter 2 - Oncogenes and Signal Transduction
		Signaling: An Overview
		Oncogenes
		Signal Transduction by Protein Tyrosine Kinase Receptors
		Signaling Pathways of Tyrosine Kinase Receptors
		Oncogenes and Survival Signaling
		Cytokine Receptor Signaling
		Neurotransmitters
		Wnt Signaling
		Hedgehog/Patched Signaling
		Implications for Cancer Therapy
		References
	Chapter 3 - Tumor Suppressor Genes
		Introduction
		Complications of Tumor Suppression
		Interconnecting the pRB, p53, and mTORC1 Pathways
		Epigenetic Modifications and Tumor Suppression
		Conclusions
		References
	Chapter 4 - DNA Repair Pathways and Human Cancer
		Introduction
		The Spectrum of DNA Damage
		The Systematic Study of DNA Repair
		DNA Repair and the DNA Damage Response
		Prognostic and Predictive DNA Repair Biomarkers in Cancer Treatment
		The Development of New DNA Repair Biomarkers
		Multiple Mechanisms of Cisplatin Resistance
		Conclusion
		References
	Chapter 5 - Epigenetics and Cancer
		The Molecular Basis for Epigenetic Control of Gene Expression
		Abnormalities of DNA Methylation and Chromatin Organization in Cancer: The Cancer “Epigenome”
		Translational Implications of Epigenetic Changes in Cancer
		References
	Chapter 6 - Infectious Agents and Cancer
		Overview of Cancer and Infectious Agents
		Viruses and Cancer
		Bacteria and Cancer
		Parasites and Cancer
		Perspectives
		References
	Chapter 7 - Environmental Carcinogenesis
		Introduction to Cancer and the Environment
		Causes of Cancer
		Classes and Types of Carcinogens
		Mechanisms of Chemical Carcinogenesis
		Endogenous Defense Systems against Chemical Carcinogenesis
		Cancer Prevention
		Summary and Conclusions
		References
	Chapter 8 - Animal Models: Flies, Fish, and Yeast
		Why Use a Simple Model Organism?
		Genetic Conservation and Synteny
		Forward Genetics, Reverse Genetics, and Transgenesis
		Drug Screens
		Conditional Models
		Yeast
		Flies
		Fish
		Conclusion
		References
	Chapter 9 - Genetic Mouse Models of Cancer
		Basis for Mouse Models of Cancer
		Mouse Models of Cancer
		Applications of Mouse Models to Cancer Biology
		Future Directions of Cancer Models
		Conclusions
		References
IICancer biology
	Chapter 10 - Cancer Stem Cells and the Microenvironment
		Identification of Cancer Stem Cells
		Cytokine Networks Can Promote Cancer Stem Cell Self-Renewal
		Summary
		References
	CHAPTER 11 - Regulation of the Cell Cycle
		Basic Principles of Cell Cycle Progression
		The Cyclin-Dependent Kinases
		Posttranslational Regulation of CDKs
		Transcriptional Regulation by the E2F Transcription Factors
		G1 Regulation/Restriction Point Control
		Regulation of DNA Replication (S Phase)
		G2/M Transition Regulation
		Regulated Proteolysis in Cell Cycle Control
		Deregulation of G1 Restriction Point Control in Cancer
		Targeting the Cell Cycle as a Therapeutic Modality
		Conclusions
		References
	Chapter 12 - Cell Growth
		What Is Cell Growth?
		Biochemical Pathways That Control Cell Growth
		Beyond Cell Growth: Does mTOR Regulate Organ and Organism Growth?
		Key References
		References
	Chapter 13 - The Metabolism of Cell Growth and Proliferation
		Why Is Metabolism Important to an Understanding of Cancer?
		The Metabolic Requirements of Cell Proliferation
		Regulation of Cell Metabolism
		The Metabolic Profile of Cancer Cells
		Genetic Mechanisms Driving Cancer Cell Metabolism
		Clinical Implications of Metabolic Transformation
		References
	Chapter 14 - Apoptosis, Necrosis, and Autophagy
		The Ways Cells Die
		Apoptosis
		Necrosis
		Autophagy
		References
	CHAPTER 15 - Cellular Senescence
		Biochemical and Morphological Characteristics of Senescent Cells
		Replicative Senescence and the Hayflick Limit
		Conclusions and Perspectives
		References
	Chapter 16 - The Role of the Microenvironment in Tumor Initiation, Progression, and Metastasis
		Promoting Microenvironments
		Suppressive Microenvironments
		The Tumor Organ
		The Frontiers of the Microenvironment
		Acknowledgements
		References
	CHAPTER 17 - Tumor Angiogenesis
		Vascular Development
		Critical Signaling Factors—Targets for Therapy
		Targeting Tumor Angiogenesis in Patients
		Remaining Challenges
		References
	Chapter 18 - Invasion and Metastasis
		Generation of a Metastatic Cell
		Tumor Invasion
		Adhesion
		Matrix Degradation
		Motility
		Coordination of Cancer Invasion
		The Metastatic Cascade
		Intravasation
		Transport
		Arrest
		Extravasation
		Colonization
		Organ Selectivity of Metastasis
		Metastatic Progression
		Colonization and Interactions with the Tumor Microenvironment
		References
	Chapter 19 - Inflammation and Cancer
		Introduction
		Hematopoiesis and the Immune System
		Chronic Inflammation and Tumor Incidence
		Inflammation and the Metastatic Cascade
		Immune Cells in Cancer
		Nonhematopoietic Stromal Cell Types in the Tumor Microenvironment
		Summary
		Key References
		References
	Chapter 20 - Cancer Systems Biology: The Future
		Reverse Engineering Regulatory Networks
		Interrogating Pathways and Networks
		Using Regulatory Networks to Elucidate Drug Activity
		Recent Trends and Future Perspectives
		The Technologies of Cancer Systems Biology
		References
IIIMolecular pathology and Diagnostics
	Chapter 21 - Biomarkers for Assessing Risk of Cancer
		Biomarkers of Exposure
		Biomarkers of Effect
		Biomarkers of Susceptibility
		Integrative Multifactor Risk Prediction
		Conclusion
		References
	Chapter 22 - Protein Biomarkers for Detecting Cancer: Molecular Screening
		Defining “Normal”
		Completeness of Shotgun Biomarker Discovery Proteomics
		MS Protein Profiling
		The Proteomics Toolbox for Biomarker Discovery and Validation
		Example: Biomarker Development Using a Mouse Model of Human Breast Cancer
		Conclusions
		References
	Chapter 23 - The Technology of Analyzing Nucleic Acids in Cancer
		Introduction to Next-Generation Sequencing
		Challenges to NGS Analysis of Cancer Nucleic Acids
		Applications of NGS to Study and Analyze Nucleic Acids
		Conclusions
		References
	Chapter 24 - Understanding and Using Information about Cancer Genomes
		The Emerging Cancer Genome Landscape
		Functional Assessment of Cancer Genomes
		Clinical Applications
		Summary
		References
	Chapter 25 - High-Content Analysis with Cellular and Tissue Systems Biology: A Bridge between Cancer Cell Biology and Tissue-Based Diagnostics
		High-Content Analysis (HCA)
		Cellular Systems Biology in Cancer Research and Drug Discovery
		Tissue Systems Biology in Cancer Diagnostics/Prognostics
		Conclusion and Outlook
		References
IVMolecular pathogenesis and Therapeutic targets for specific Cancers
	Chapter 26 - Molecular Genetics of Acute Lymphoblastic Leukemia
		Introduction
		Prognostic Factors
		Overview of Molecular Genetics of ALL
		Abnormalities of Chromosome Number (Ploidy)
		Genetic Abnormalities in ALL
		Clinical Implications of Genetic Lesions in ALL
		Conclusions
		References
	Chapter 27 - Molecular Biology of Childhood Neoplasms
		Retinoblastoma
		Wilms Tumor
		Tumors of the Peripheral Nervous System: Neuroblastoma
		Rhabdomyosarcoma
		Childhood Sarcomas: Osteosarcoma
		Cancer Predisposition Syndromes
		Molecular and Clinical Surveillance for Cancer Predisposition in Children
		References
	Chapter 28 - Biology of Adult Myelocytic Leukemia and Myelodysplasia
		Introduction
		Acute Myeloid Leukemia
		Molecular Pathogenesis of AML
		Mutations Altering Signal Transduction
		Myelodysplastic Syndromes
		Concluding Remarks
		References
	Chapter 29 - Lymphoma
		B- and T-Lymphocyte Development
		Pathogenesis of Diffuse Large B-Cell Lymphoma
		Molecular Pathogenesis of Follicular Lymphoma
		Pathogenesis of Mantle-Cell Lymphoma
		Molecular Pathogenesis of the Peripheral T-Cell Lymphomas
		Translating Molecular Pathogenesis into Novel Treatment Platforms
		Future Directions
		References
	Chapter 30 - Multiple Myeloma
		Final Remarks
		References
	Chapter 31 - Molecular Mechanisms of Esophageal Cancer
		Introduction
		Histology
		Etiology and Molecular Mechanisms of Esophageal Cancer
		Chronic Inflammation and Esophageal Cancer
		Environmental Carcinogenic Exposures and Esophageal Cancer
		References
	Chapter 32 - Molecular Basis of Lung Cancer
		Molecular Epidemiology and Etiology
		Genomics: Tools for Identification, Prediction, and Prognosis
		Epigenetic Changes in Lung Carcinogenesis
		Oncogenes, Tumor Suppressor Genes, and Signaling Pathways in Lung Cancer
		Translation of Molecular Data to the Clinic: Rationale-Based Targeted Therapy
		References
	Chapter 33 - The Molecular Pathogenesis of Head and Neck Cancer
		Epidemiology and Clinical Considerations
		Oncogenic Progression of HNSCC
		Molecular Pathogenesis of HNSCC: Interfacing Genomic Pathways
		Cell Cycle and Proliferation: TP53/CDKN2A/RB/CCND1/TERT
		Apoptosis and Survival: EGFR/RAS-MAPK/PIK3CA-AKT/CASP8
		Differentiation and Mesenchymal Transition: NOTCH/TP63
		Invasion and Metastasis: MMP/TGFβ-SMAD/NFκB/CSMD/VEGF
		Future Directions
		References
	Chapter 34 - Colon and Rectal Cancer
		Epidemiology
		Recurrent Somatic Alterations in Colorectal Cancer
		Multistep Genetic Models of Colorectal Tumor Development
		Clinical Applications of Molecular Genetic Insights
		Summary and Future Directions
		References
	Chapter 35 - Molecular Pathogenesis of Pancreatic Adenocarcinoma
		Molecular Alterations in Pancreatic Cancer
		Conclusion
		References
	Chapter 36 - The Molecular Biology of Breast Cancer
		Molecular Biology of Breast Cancer Initiation and Progression
		Pathophysiology and Risk Factors
		Environment
		Molecular Subtyping
		Molecular Basis of Breast Cancer
		Conclusion and Outlook
		Acknowledgments
		References
	Chapter 37 - Molecular Pathogenesis of Ovarian Cancer
		Cellular and Molecular Characteristics of Ovarian Cancer Cells
		Immortalization
		Genomic Abnormalities in Sporadic Ovarian Cancers
		Interaction of Ovarian Cancer Cells with the Microenvironment
		Immunologic and Inflammatory Factors
		Conclusion
		References
	Chapter 38 - Molecular Basis of Prostate Cancer
		Pathology
		Molecular Pathology
		Polycomb Group Transcriptional Repression
		Future Directions
		References
	Chapter 39 - Molecular Abnormalities in Kidney Cancer
		Kidney Cancer Histopathology
		Common Somatic Alterations in Clear Cell Renal Carcinoma
		Inactivation of Tumor Suppressor Genes
		Multistep Genetic Models of Clear Cell Renal Carcinoma
		Common Somatic Alterations in Non–Clear Cell Renal Carcinoma
		Clinical Applications of Molecular Insights
		Therapy (Clear Cell)
		Therapy (Non–Clear Cell)
		Prognostic and Predictive Markers
		Summary and Future Directions
		References
	Chapter 40 - The Biology of Primary Brain Tumors
		Hereditary Syndromes and Central Nervous System Oncogenesis
		Molecular Biology of the Most Common Primary Central Nervous System Tumors
		Molecular Pathophysiology of Primary Brain Tumors
		Therapeutic Resistance of Primary Central Nervous System Tumors
		Future Directions/Perspective
		References
	Chapter 41 - Epithelial Skin Cancer
		Skin Cancer Research Has Helped Define the Biology of Cancer Pathogenesis
		The Molecular Origin of Skin Tumors Is Revealed by Hereditary Syndromes
		Basal Cell Carcinoma
		Cutaneous Squamous Cell Carcinoma
		Defining the Cell of Origin for Cutaneous Cancers
		Importance of the Microenvironment in Cutaneous Cancer
		Perspective
		References
	Chapter 42 - Molecular Basis for Treating Cutaneous Molecular
		Introduction
		Melanoma Background
		Melanoma Pathology
		Melanoma Therapy and Molecular Targets
		Epigenetic Pathways: MicroRNA
		Conclusions
		References
	CHAPTER 43 - Thyroid Cancer
		Differentiated Thyroid Carcinoma
		Medullary Thyroid Carcinoma
		Other Molecular Mechanisms Active in Thyroid Carcinoma
		Therapeutic Targeting
		Future Directions
		References
	Chapter 44 - Soft Tissue Sarcomas
		Introduction
		Synovial Sarcoma
		Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
		Gastrointestinal Stromal Tumor
		Conclusion
		References
V -Molecular basis of cancer therapy
	Chapter 45 - From Bench to Bedside with Targeted Therapies
		Drug Development
		Next Steps in Drug Development
		Conclusion
		References
	Chapter 46 - Cancer Therapeutics
		Molecular Basis of the Therapeutic Index
		Drugs Affecting Growth Factors and Growth Factor Receptors
		Drugs That Target Cancer Stem Cells
		Drugs That Target the Immune System
		Drugs That Alter Nucleic Acid Synthesis and Function
		Drugs that Affect the Mitotic Apparatus
		Drugs That Affect Protein Synthesis and Degradation
		References
	Chapter 47 - Natural and Acquired Resistance to Cancer Therapies
		Pharmacologic and Physiologic Causes of Treatment Failure
		Cellular Mechanisms of Drug Resistance
		References
	Chapter 48 - Phase I Trials Today
		Introduction
		Types of Phase I Clinical Trials
		Phase I Cancer Clinical Trial Designs
		Statistical Considerations of Phase I Studies
		Pharmacodynamic Markers in Phase I Studies: Tissue Analysis
		Recent Therapeutic Successes with Phase I Trials
		Challenges and Perspectives
		Imaging Techniques in Phase I Studies
		Conclusion
		References
	Chapter 49 - Pharmacogenomics
		Introduction
		Pharmacogenomics in Oncology
		Genotyping and Phenotyping
		Pharmacogenomic Discovery Approaches
		Clinical Relevance of Pharmacogenomic Findings During Implementation
		Conclusions
		References
	Chapter 50 - Monoclonal Antibodies for the Treatment of Cancer
		Introduction
		Antibody Structure and Function
		Development of Monoclonal Antibodies
		Mechanisms of Action of Anti-Cancer Antibodies
		Antibodies Targeting Solid Tumors
		Antibodies Targeting Hematological Malignancies
		Antibodies Targeting Immune Cells
		Antibodies Targeting Angiogenesis
		Antibody Engineering
		Summary and Future Directions
		References
	Chapter 51 - Cancer and the Cellular Immune Response
		Introduction
		Innate Recognition of Microbial Pathogens by Toll-Like Receptors
		The Nature of Antitumor Immunity
		Cancer Vaccines, Cytokines, and Immunotherapy
		Adoptive Immunotherapy of Cancer
		Immune Regulatory Cells and Molecules in Human Cancer
		Immune Checkpoint Blockade
		Future Cancer Immunotherapies Will Use Basic Principles of Cellular Immunity
		References
	Chapter 52 - Cancer Immunotherapy with Vaccines and Checkpoint Blockade
		Cancer Antigens—the Difference between Tumor and Self
		Evidence Pro and Con for Immune Surveillance of Cancer
		Immune Tolerance and Immune Evasion—the Immune Hallmarks of Cancer
		Inhibition of Antitumor Immunity by Regulatory T Cells
		Therapeutic Cancer Vaccines
		Evidence of Clinical Activity for PD-1 Blockade
		Summary
		References
	Chapter 53 - Interferons
		Introduction
		Induction, Genes, Receptors, and Signaling
		Mechanisms of Antitumor Action of Induced Genes
		Antitumor Effects in Humans
		Perspective
		References
	Chapter 54 - Gene Therapy and Oncolytic Viruses
		Introduction
		Killing Cancer Cells by Gene Replacement and Gene Knockout
		Genes That Boost the Immune System
		Naturally Occurring Viruses That Replicate Selectively in Cancer Cells
		Viruses Engineered to Replicate Selectively
		Challenges and Future Perspective
		Conclusion
		References
	Chapter 55 - RNA as a Therapeutic Molecule
		Cancer as a Genetic Disease of Protein-Coding Genes and Noncoding RNAs
		Main Types of Therapeutic RNA Molecules
		In Search of the Right Way and the Right Type of Delivery
		A Strategy for Using RNA as Therapeutic Molecules
		References
	Chapter 56 - Heat Shock Protein 90 and the Proteasome: Housekeeping Proteins That Are Also Molecular Targets for Cancer Therapy
		Introduction
		Hsp90: a Chaperone of Cancer
		The Proteasome as an Anticancer Molecular Target
		Why Are Tumor Cells Uniquely Sensitive to Hsp90 and Proteasome Inhibition?
		Conclusion
		References
	Chapter 57 - Hematopoietic Growth Factors and Cytokines
		Erythropoietin
		Granulocyte-Macrophage Colony-Stimulating Factor
		Granulocyte Colony-Stimulating Factor
		Macrophage Colony-Stimulating Factor
		Stem-Cell Factor
		Thrombopoietin
		Interleukin-1
		Interleukin-2
		Interleukin-3
		Interleukin-4 and Interleukin-13
		Interleukin-5
		Interleukin-6
		Interleukin-7
		Interleukin-8
		Interleukin-9
		Interleukin-10
		Interleukin-11
		Interleukin-12
		Interleukin-15
		Interleukin-16
		Interleukin-17
		Interleukin-18
		Interleukin-19
		Interleukin-20
		Interleukin-21
		Interleukin-22
		Interleukin-23
		Interleukin-24
		Interleukin-25
		Interleukin-26
		Interleukin-27
		Interleukin-28 and Interleukin-29
		Interleukin-31
		Interleukin-32
		Interleukin-33
		Interleukin-35
		Interleukin-36
		Interleukin-37
		Interleukin-38
		Conclusion
		References
	Chapter 58 - Cancer Chemoprevention
		Molecular-Targeted Prevention
		Biomarker Cancer Risk Models
		Chemoprevention Trials
		Conclusion
		References
	Chapter 59 - Molecular Pathology
		Processing Cancer Specimens for Microscopic Evaluation
		Special Stains for Evaluating Cancer Tissues
		Preparing Nucleic Acids from Cancer Specimens
		Assays for Single Genes or Single Mutations
		Multiplexed Approaches to Cancer Genotyping
		Next-Generation DNA Sequencing
		Future Directions
		References
Index
IBC